Our long-range goal is to develop methodologies for drug design based on free energy calculations. We wish to obtain a better understanding of the physical principles that govern the interaction between drugs and proteins. To this end we plan to carry out free energy calculations on HIV-1 protease complexed with various inhibitors for which crystal structures and binding constants are available to us. Particular emphasis will be placed on parameterization of the force field and sampling of the conformations of the protein/inhibitor complex and of the free inhibitor. Macroscopic approaches that have been suggested recently by various groups to estimate free energies of binding will be tested and their utility for data base searches evaluated. Our efforts will include the reverse transcriptase protein of HIV as soon as appropriate high-resolution data on inhibitor complex become available.